LRIG2 is an N-glycosylated type-I single-pass membrane protein whose extracellular region contains 15 leucine-rich repeats and three immunoglobulin-like domains. It acts as a context-dependent regulator of cell-surface receptors through its ectodomain rather than as a signaling receptor or enzyme itself. In human glioblastoma models, full-length LRIG2 binds EGFR and PDGFRB and increases their abundance and signaling, while a soluble LRIG2 ectodomain recovered from conditioned medium retains EGFR binding and growth-promoting activity. Biallelic loss of LRIG2 causes urofacial syndrome type 2, and LRIG2 is present in developing human bladder nerve fascicles, linking it to neural development of the lower urinary tract. Mouse Lrig2 additionally supports auditory neuronal output and regulates Neogenin shedding during neuronal development.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference places LRIG2 activity at the plasma membrane, consistent with the experimentally reviewed human cell-membrane localization and its single-pass type-I membrane topology. Reason: Plasma membrane is a defining location for full-length LRIG2. Although the IBA source set spans a broad group of LRR/Ig membrane proteins, the transfer is independently supported for human LRIG2 by UniProt experimental localization and by direct human interaction studies that detect LRIG2 at the plasma membrane. Propagation Review Root cause: NO FAILURE CORE Sources checked: FB:FBgn0034476 MGI:MGI:107935 MGI:MGI:1333744 MGI:MGI:1915522 MGI:MGI:2177651 MGI:MGI:2389177 MGI:MGI:2389180 MGI:MGI:2442479 MGI:MGI:3608416 PANTHER:PTN001224703 RGD:1560707 RGD:1585921 RGD:727797 UniProtKB:O15455 UniProtKB:P07359 UniProtKB:Q14392 UniProtKB:Q86UE6 UniProtKB:Q86UN2 UniProtKB:Q86UN3 UniProtKB:Q8TF66 UniProtKB:Q96FE5 UniProtKB:Q96JA1 UniProtKB:Q99467 WB:WBGene00020649 |
| GO:0038023 signaling receptor activity | IBA GO_REF:0000033 | REMOVE | Summary: A broad PANTHER IBA assigns signaling receptor activity from a mixed LRR receptor-family node rather than from LRIG2-specific receptor evidence. Reason: Signaling receptor activity requires receiving and transmitting a signal. Human LRIG2 is instead experimentally supported as a single-pass modulator that binds EGFR and PDGFRB and alters their signaling. The IBA source set includes bona fide receptors TLR3, CD180, RTN4RL1, and RTN4RL2, so receptor activity must not be transferred across this broad family boundary to LRIG2. LRIG1/3 biology likewise does not establish LRIG2 as a receptor. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG ROLE CONFLATION Sources checked: FB:FBgn0034476 PANTHER:PTN002809265 RGD:727797 UniProtKB:O15455 · TLR3 SUPPORTS SOURCE BUT NOT TARGET UniProtKB:Q86UN2 · RTN4RL1 SUPPORTS SOURCE BUT NOT TARGET UniProtKB:Q86UN3 · RTN4RL2 SUPPORTS SOURCE BUT NOT TARGET UniProtKB:Q99467 · CD180 SUPPORTS SOURCE BUT NOT TARGET |
| GO:0007605 sensory perception of sound | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic inference transfers an auditory-process role from mouse Lrig genes; the source set includes mouse Lrig2 itself, whose loss impairs auditory neural output despite normal sound-detection thresholds. Reason: The true mouse Lrig2 ortholog provides relevant genetic support, so this is not merely an LRIG1 paralog transfer. Sensory perception of sound is nevertheless a specialized organismal consequence rather than LRIG2's defining molecular role, and direct human auditory evidence is absent. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: MGI:MGI:107935 · mouse Lrig1 SUPPORTS TRANSFER MGI:MGI:2443718 · mouse Lrig2 SUPPORTS TRANSFER The official MGI Gene Detail record identifies MGI:2443718 as mouse Lrig2 (leucine-rich repeats and immunoglobulin-like domains 2), not Lrig3. The repository's PANTHER entry independently places mouse Q52KR2/Lrig2 in the LRIG2-related subfamily PTHR45842:SF23. PANTHER:PTN009094493 · LRIG auditory-function ancestral node SUPPORTS TRANSFER |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular-location mapping assigns LRIG2 to the cytoplasm, consistent with experimental human staining and the protein's cytoplasmic tail. Reason: The broad cytoplasm location is supported, but it is secondary to the defining plasma-membrane topology and can include intracellular pools of full-length LRIG2. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0086 · UniProt Cytoplasm location SUPPORTS TRANSFER |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping places LRIG2 at the plasma membrane, matching experimentally reviewed human cell-membrane localization and type-I topology. Reason: Plasma membrane is the specific and defining location for full-length LRIG2 and is independently concordant with its signal peptide, transmembrane helix, and direct human interaction studies. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0039 · UniProt Cell membrane location SUPPORTS TRANSFER |
| GO:0005515 protein binding | IPI PMID:25353163 Soluble LRIG2 ectodomain is released from glioblastoma cells... | MODIFY | Summary: Co-localization and co-immunoprecipitation in human glioblastoma cells show that full-length LRIG2 and its soluble ectodomain physically interact with EGFR. Reason: The interaction is directly supported, but generic protein binding obscures the tested receptor specificity. GO:0005154 epidermal growth factor receptor binding captures the molecular function without importing LRIG1's opposite regulatory sign or generalizing to other LRIG paralogs. Proposed replacements: epidermal growth factor receptor binding Supporting Evidence: PMID:25353163 through physically interacting with EGFR, stabilizing EGFR, and enhancing EGFR activation PMID:25353163 As illustrated in Figure 7A, LRIG2 was found largely in the intracellular cytoplasm as well as in the plasma membrane and EGFR exhibited a similar distribution. |
| GO:0005515 protein binding | IPI PMID:30015847 LRIG2 promotes the proliferation and cell cycle progression ... | MODIFY | Summary: Reciprocal co-immunoprecipitation in human U87 glioblastoma cells supports a physical interaction between LRIG2 and PDGFRB. Reason: The interaction is direct enough for a receptor-specific binding term. Replacing generic protein binding with GO:0005161 platelet-derived growth factor receptor binding reflects the tested PDGFRB partner while avoiding transfer of EGFR or LRIG1-specific activities. Proposed replacements: platelet-derived growth factor receptor binding Supporting Evidence: PMID:30015847 indicating that LRIG2 physically associates with PDGFRβ. PMID:30015847 In the present study, it was demonstrated that LRIG2 could physically interact with PDGFRβ in the cytoplasm and increase the PDGF-BB-induced total expression level and phosphorylation of PDGFRβ, which was in line with the effects of LRIG2 on EGFR (22). |
| GO:0005102 signaling receptor binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl transfers broad signaling-receptor binding from the true mouse Lrig2 ortholog; direct human experiments independently demonstrate binding to EGFR and PDGFRB. Reason: The ortholog transfer is sound and the broad parent term is independently corroborated by receptor-specific human interactions, but GO:0005102 is less informative than the separately reviewed EGFR- and PDGFR-binding terms. It is retained as a valid broad parent without treating it as a distinct core activity. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q52KR2 · mouse Lrig2 SUPPORTS TRANSFER ensembl:ENSMUSP00000035999 · mouse Lrig2 protein SUPPORTS TRANSFER Supporting Evidence: PMID:25353163 through physically interacting with EGFR, stabilizing EGFR, and enhancing EGFR activation PMID:30015847 indicating that LRIG2 physically associates with PDGFRβ. |
| GO:0016020 membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl transfers the broad membrane location from the true mouse Lrig2 ortholog. Reason: Membrane localization is correct for this single-pass protein, but GO:0016020 is less informative than the independently supported plasma-membrane annotations. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q52KR2 · mouse Lrig2 SUPPORTS TRANSFER ensembl:ENSMUSP00000035999 · mouse Lrig2 protein SUPPORTS TRANSFER |
| GO:0030426 growth cone | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl transfers growth-cone localization from the true mouse Lrig2 ortholog, which has a documented neuronal role in regulating axon-guidance receptor ectodomain shedding. Reason: The true-ortholog transfer is biologically coherent and does not depend on LRIG1 or LRIG3. Growth-cone localization is nevertheless a specialized neuronal context not directly demonstrated for human LRIG2, so it is retained as non-core. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q52KR2 · mouse Lrig2 SUPPORTS TRANSFER ensembl:ENSMUSP00000035999 · mouse Lrig2 protein SUPPORTS TRANSFER |
| GO:0097708 intracellular vesicle | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl transfers intracellular-vesicle localization from the true mouse Lrig2 ortholog, consistent with intracellular pools of the membrane protein. Reason: The localization is plausible and comes from the one-to-one mouse ortholog rather than an LRIG paralog, but it is contextual and lacks direct human vesicle evidence. It should not displace plasma membrane as the defining location. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q52KR2 · mouse Lrig2 SUPPORTS TRANSFER ensembl:ENSMUSP00000035999 · mouse Lrig2 protein SUPPORTS TRANSFER |
| GO:0045742 positive regulation of epidermal growth factor receptor signaling pathway | IMP PMID:25353163 Soluble LRIG2 ectodomain is released from glioblastoma cells... | NEW | Summary: Overexpression of full-length human LRIG2 or its ectodomain in U87 and U251 glioblastoma cells increased EGFR abundance and phosphorylation and enhanced downstream PI3K/Akt signaling. Reason: Direct perturbation and pathway readouts support positive regulation of the EGFR signaling pathway in the tested glioblastoma models. This annotation does not establish the same regulatory direction in normal human cells and does not transfer the negative EGFR-regulatory mechanism of LRIG1. Supporting Evidence: PMID:25353163 Remarkably, in the present study we for the first time demonstrated that full-length LRIG2 and LRIG2 ectodomain both could physically interact with EGFR, increase the level of EGFR and enhance the activation of EGFR and its downstream PI3K/Akt pathway, resulting in increment of pro-proliferative and anti-apoptotic proteins and attenuation of pro-apoptotic proteins. |
| GO:2000588 positive regulation of platelet-derived growth factor receptor-beta signaling pathway | IMP PMID:30015847 LRIG2 promotes the proliferation and cell cycle progression ... | NEW | Summary: LRIG2 overexpression and knockdown in human U87 glioblastoma cells altered PDGFRB abundance, activation, and downstream Akt and STAT3 signaling. Reason: Bidirectional perturbation and receptor-specific pathway readouts license the beta-receptor-specific positive-regulation term in this glioblastoma context. The result is not generalized to normal physiology because mouse embryonic fibroblasts showed no corresponding effect on PDGFR abundance or phosphorylation. Supporting Evidence: PMID:30015847 progression. Mechanistically, LRIG2 has the ability to physically interact with PDGFRβ, promoting the total expression and the activation of PDGFRβ, and enhancing its downstream signaling pathways of Akt and signal transducer and activator of transcription 3 and the effectors of key regulators of cell cycle progression, resulting in increased GBM cell proliferation. Collectively, these |
| GO:0005576 extracellular region | IDA PMID:25353163 Soluble LRIG2 ectodomain is released from glioblastoma cells... | NEW | Summary: An N-terminally tagged fragment with the expected size of the LRIG2 ectodomain was detected in conditioned medium from glioblastoma cells overexpressing full-length human LRIG2. Reason: The experiment directly supports extracellular localization of a soluble LRIG2 ectodomain. It does not establish the release mechanism, identify a protease, or place full-length membrane-anchored LRIG2 in the extracellular region. Supporting Evidence: PMID:25353163 the soluble LRIG2 ectodomain was capable of being secreted by glioblastoma cells. |
| GO:0051045 negative regulation of membrane protein ectodomain proteolysis | ISO PMID:26651291 Lrig2 Negatively Regulates Ectodomain Shedding of Axon Guida... | NEW | Summary: Mouse Lrig2 binds Neogenin and prevents premature ADAM17-mediated Neogenin ectodomain shedding in neurons. Reason: The one-to-one mouse ortholog directly supports this species-bounded mechanism. ISO transfers the conserved Lrig2 role to human LRIG2 while explicitly avoiding a claim that the Neogenin interaction or neuronal output has been demonstrated in normal human cells. Supporting Evidence: PMID:26651291 repulsive guidance molecules (RGMs), and prevents premature Neogenin shedding by ADAM17 (TACE). |
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Download this section (compressed HTML)Q: Which endogenous receptors does LRIG2 bind and regulate in normal human neural and lower-urinary-tract cells, and is the direction of regulation the same as in glioblastoma cells?
Q: By what route is the soluble LRIG2 ectodomain released, and what sequence or cellular determinants govern release without assuming LRIG1-like proteolysis?
Q: Which LRIG2-dependent receptor and circuit defects cause urofacial syndrome type 2, and do they involve Neogenin regulation in humans?
Q: Does human LRIG2 regulate Neogenin ectodomain shedding in developing neurons, and does this mechanism contribute to urinary-tract innervation or auditory function?
Experiment: Endogenously tag and acutely deplete LRIG2 in human autonomic-neuron and bladder organoid co-cultures, identify surface-proximal partners by quantitative proximity labeling, and test receptor abundance, phosphorylation, and downstream signaling after wild-type rescue. Include EGFR, PDGFRB, and Neogenin as prespecified candidates and LRIG1/3 perturbations as paralog controls.
Hypothesis: Endogenous LRIG2 regulates a restricted receptor set in normal human neural and lower-urinary-tract cells, with effects that differ from glioblastoma signaling.
Type: endogenous perturbation, proximity proteomics, and signaling analysis
Experiment: Introduce separate extracellular and cytoplasmic tags at the endogenous LRIG2 locus, perform pulse-chase sampling with soluble and extracellular-vesicle fractionation, map released termini by N-terminomics and C-terminomics, and perturb candidate protease and vesicle pathways before testing purified fractions for EGFR binding.
Hypothesis: Soluble LRIG2 ectodomain is generated by a regulated release pathway and retains a receptor-binding activity distinct from extracellular vesicle-associated full-length protein.
Type: endogenous tagging, secretion-route analysis, and terminomics
Experiment: Generate patient-derived and isogenic-corrected induced pluripotent stem cell models, differentiate autonomic neurons, and co-culture them with bladder smooth-muscle organoids. Measure neurite targeting, synaptic connectivity, evoked muscle responses, and candidate-receptor signaling, with canonical LRIG2 rescue and pathway epistasis.
Hypothesis: Urofacial-syndrome LRIG2 loss disrupts a receptor-dependent developmental program in autonomic neurons that innervate the bladder.
Type: disease modeling, genetic rescue, and neural circuit physiology
Experiment: Endogenously disrupt or repair LRIG2 in human autonomic and auditory-neuron models, quantify LRIG2-Neogenin proximity, surface Neogenin, soluble Neogenin ectodomain, ADAM17 dependence, neurite growth, and migration, and rescue with interaction- competent or interaction-defective LRIG2.
Hypothesis: Human LRIG2 conserves the mouse Lrig2-Neogenin checkpoint that restrains premature ADAM17-mediated ectodomain shedding during neuronal development.
Type: human neuronal Neogenin-shedding mechanism test
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The endogenous receptor partners and direction of LRIG2-mediated signaling regulation in normal human tissues are unknown.
OPEN BIOLOGY MF_DARK
What is known: Human glioblastoma-cell perturbations support EGFR and PDGFRB binding and positive pathway regulation, whereas the human developmental evidence establishes disease causality and neural localization without identifying a receptor mechanism.
Significance: Resolving this gap is necessary to distinguish a general physiological receptor regulator from a signaling behavior created or amplified by glioblastoma context.
What would resolve it: Perturb endogenous LRIG2 in normal human neural and lower-urinary-tract models and quantify candidate-receptor binding, abundance, activation, and downstream signaling with receptor-specific rescue and epistasis.
Provenance (the field's own admissions):
Gap: The cellular mechanism that releases the soluble LRIG2 ectodomain is unknown.
OPEN BIOLOGY BP_DARK
What is known: A tagged fragment of the expected ectodomain size was recovered from conditioned medium after full-length LRIG2 expression, but this does not distinguish proteolytic cleavage from vesicular or other release routes.
Significance: The release route determines how extracellular LRIG2 is generated and regulated and whether its abundance can be manipulated independently of full-length LRIG2.
What would resolve it: Use endogenous dual-terminal tagging, pulse-chase analysis, extracellular-vesicle fractionation, unbiased terminomics, and perturbation of candidate release pathways to identify the released species and its route without presupposing a protease.
Provenance (the field's own admissions):
Gap: How LRIG2 loss causes urofacial syndrome type 2 at the molecular and circuit levels remains unresolved.
OPEN BIOLOGY BP_DARK
What is known: Biallelic human LRIG2 variants establish disease causality, and LRIG2 is detected in developing bladder nerve fascicles, but neither observation identifies the relevant receptor partner, cell type, or signaling defect.
Significance: A causal mechanism would connect LRIG2's receptor-regulatory activity to the abnormal neural control of bladder emptying and facial expression.
What would resolve it: Compare patient-derived and isogenic-corrected autonomic neural and bladder-organoid co-cultures using lineage-resolved phenotyping, receptor-interactome analysis, and functional neural-to-muscle assays.
Provenance (the field's own admissions):
Gap: It is unknown whether the mouse Lrig2-Neogenin shedding mechanism and auditory role are conserved in human LRIG2.
OPEN BIOLOGYCURATION BP_DARK
What is known: Mouse studies support regulation of Neogenin cleavage, cortical-neuron migration, and auditory neuronal responses, but no direct human assay establishes these mechanisms or phenotypes.
Significance: Direct testing is required before mouse neural mechanisms can explain human LRIG2 disease or support unqualified human GO annotations.
What would resolve it: Test endogenous LRIG2-Neogenin association, Neogenin ectodomain release, RGMa responses, and neuronal electrophysiology in human neural models with LRIG2 knockout and rescue.
Provenance (the field's own admissions):
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